ALZHEIMER’S DISEASE- UPDATED INFO SHOT · A long history of findings & failures, raise in deaths, prevalence & costs, this is how Alzheimer’s is defined Ref: Alzforum, Alz.org

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© Ingenious e-Brain Market and Technology Intelligence 2018

ALZHEIMER’S DISEASE- UPDATED INFO SHOT

A story of setback or success

Author: Anurag Pandey

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A long history of findings & failures, raise in deaths, prevalence & costs, this is how Alzheimer’s is defined

Ref: Alzforum, Alz.org

The present paper highlight the status around Alzheimer’s, it’s advanced clinical development, available treatment, economic burden and the major challenges being faced in the Alzheimer’s.

The Dementia- A loss or decline in memory and other cognitive abilities.

“Imagine an age of 65+, already lived more than half of life and then started to forget the beautiful moments of life, it’s hard to believe but one of the disease do so, and surprisingly is more responsive in case of resistance than therapy, the reason behind this is memory ignorance, called dementia”.

Alzheimer’s Disease runs parallel with dementia and has a big impact on both patient & society. Dementia term is usedin daily life with different intensity, it could be mild (forgotten any task) to moderate (problem in remembering events,performing daily tasks) and to severe (appearance of depression or anxiety, guidance in eating foods or wearing clothes)but when this common factor badly affects the daily life of person, it could be signs of irreversible, progressive braindisorder called Alzheimer’s which according to CDC is responsible for 60% to 80% of dementia cases.

According to Alz.org, there is a 123% increase in deaths due to Alzheimer’s. This death is more than combined death caused due to prostate and breast cancer. This alarm doesn’t stop here, in US 1@every 65 sec is developing Alzheimer’s

and is estimated to reach 14 Mn by 2050.

Alzheimer’s rank 6th when we talk about the cause of death, according to WHO 2016, Alzheimer’s rank higher comparedto the progressive development made in cancer, however in middle-upper countries it has been rank after lung cancerbut again in high-income countries it has been rank above lung cancers and after heart diseases.

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Funding & need of newer or modified targets have appeared as unmet area in Alzheimer’s


Aging itself comes with lots of physical and immunity-related changes & complications, this is where Alzheimer’s mostly talked, it will be not wrong if age highlighted and considered as a promoter of Alzheimer’s, with growing age Alzheimer’s risk progresses, the most diagnosed age group is >65.

Early diagnosis can prevent Alzheimer’s but proportional dementia is making it tough. The behavioral and psychological changes such as outdoor activities in nightwear, social behavior, repetitive behavior, etc. can give signs of dementia or can be correlated with Alzheimer’s disease, however, this need confirmation & hence doctor visit is recommended.

We know more about Alzheimer’s, but still quality treatment is lacking, biochemical targets such ACh, Glutamate & famous Tau-protein, etc. are targeted, but they seem to be more resisted than to be changed. Symptomatic targeted treatments & QoL are tried for years in addition to biochemical mediated targets, by various governments, organization, NGOs & Industry etc.

This is true that we deepen our understanding in Alzheimer’s, but a promising cure is still under investigation, newer risk factors & causes are coming out, but the exact cause of Alzheimer’s disease is still unknown.

Failure of clinical trials and exit of many industries from Alzheimer’s are making the disease worse while prevalence poolkeeps growing, it is estimated that there will be 82 million Alzheimer’s patients by 2030 and will cost $trillions as aneconomic burden. Various plans, initiatives have been taken by the governments and WHO to combat this mysteriousdisease. Science has a promising future and so is the treatment of Alzheimer’s.

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© Ingenious e-Brain Market and Technology Intelligence 2018Ref: Frozza et al., Front. Neurosci. 2018; Cai et al., Cell Mol Neurobiol. 2016; Heneca et al., Curr Neuropharmacol. 2011; Ponimaskin. OPERA MEDICA ET PHYSIOLOGICA. 2016; Das et al., Transl Neurodegener. 2017; NIA; Kocahan et al., Clinical Psychopharmacology and Neuroscience 2017; Alz.org; alzheimersresearchuk

Negatively affected

Neurons- transmit information via electrical and chemical signals

AD

Loss of function (communication, metabolism, and repair) and cell death

Cerebrum & Hippocampus

Eve

ry in

form

atio

n s

top

ped

Cerebrum

Cerebellum

Brain stem

Remembering, problem solving, thinking, feeling & controls movement

Coordination and balance

Automatic functions such as breathing, digestion, heart rate and blood pressure

Who operate What functions?

A

B

C

1 Hippocampus: Retrieval of memories

Amygdala: Emotional recall2

Left hemisphere: Struggle to complete the sentence3

Temporal lobe: Hard to recognize family and objects4

Frontal lobe: Personality & behavior5

Parietal lobe: Body sense6

Occiptal lobe: Shape, color, movement & dreams7

Impairment of brain areas and related functions

Brain functions are deeply affected due to Alzheimer’s causing impairment in carrying out daily activities

In Alzheimer's

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© Ingenious e-Brain Market and Technology Intelligence 2018Ref: Frozza et al., Front. Neurosci. 2018; Cai et al., Cell Mol Neurobiol. 2016; Heneca et al., Curr Neuropharmacol. 2011; Ponimaskin. OPERA MEDICA ET PHYSIOLOGICA. 2016; Das et al., Transl Neurodegener. 2017; NIA; Kocahan et al., Clinical Psychopharmacology and Neuroscience 2017; Alz.org; alzheimersresearchuk

Advance patho-physio-factors associated with Alzheimer

Path

op

hysio

log

y in A

D

Aβ

Hypothalamus

Dendrites

Neuronal information

BACE

ApoE

PPARγ

Serotonin Brain stem

Decision-making, behavioral control

RAGE

Dopamine

NMDA

Synaptic plasticity Memory & learning

Pathophysiology has not fully established in Alzheimer’s and targets are still missing

Negatively affectedBio/chemical/targets

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19801971

19901981

Detection of brain atrophy; Isolation of neurofibrillary tangles; NIA established; Cholinergic hypothesis; MMSE to screen mental status

Identification of Tau protein; NINCDS-ADRDA criteria; Tau cloned; NIA launches ADCS, Leon Thal’stacrine trial; Cognitive impairment correlates with synaptic damage; Alpha cleavage of APP precludes Aβ formation

Advance research continued from 70’s to 90’s while extensive modern research & findings obtained from 90’s onwards

❖ Braak staging of AD neuropathology defined;❖ First APP transgenic mouse model; ❖ AD signature found in CSF: tau increased, Aβ42

decreased; ❖ Concept of cognitive reserve articulated; ❖ Amyloid hypothesis marks conceptual shift from

descriptive to mechanistic view;❖ APP Swedish mutation found at BACE cleavage site; ❖ Microvasculature in brain is damaged in AD; ApoE4 major

risk factor for late-onset AD;❖ Mutations in presenilin-1 & 2 cause autosomal dominant

AD; ❖ ApoE influences amyloid deposition in mouse models; ❖ Alzforum launched; incidence doubles every 5 years after

65; ❖ BACE1 cloned and identified as β-secretase;❖ First Aβ active immunotherapy in mice;

ApprovalDonepezilTacrine

20001991

Rivastigmine

❖ Stages of amyloid pathology published;❖ BACE1 knockout mice; First transgenic rat models; ❖ Nonhuman primate models; Launch of ADNI; ❖ Alzheimer’s Prevention Initiative launched; ❖ Tau propagation hypothesis articulated;❖ Congress passes National Alzheimer’s Project Act; GAP

launched; European Prevention of Alzheimer’s Dementia Consortium launched; Alzheimer's Accountability Act signed into law;

❖ Incidence of dementia decreases in developed countries;

❖ Amyloid load, ApoE, subjective memory complaints predict fastest decline in preclinical AD;

❖ FDA approves first amyloid tracer, florbetapir; ❖ First demonstration of tau immunotherapy in mice❖ Negative Trials at CTAD are highlighted❖ Tau Immunotherapy for Aβ proposed

MemantineGalantamine

20172000


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❖ Trouble in remembering names

❖ Trouble while meeting to new people

❖ Forgetting just recent read materials

❖ Work tasks performance becoming poor

❖ Management failure associated with planning or organizing

MILD

❖ Forgetting events or details about personal history

❖ Feeling moody or withdrawn, especially in pschyo-social conditions

❖ Trouble in recalling their own address

❖ Disturbances in sleeping patterns

❖ Personality and behavioral changes such as repetitive behavior

MODERATE

❖ Always seeks attention in performing daily activities

❖ Severe memory impairment such as loss of recent incidents

❖ Impairment of physical performance & communications

❖ Raise in chances of getting pneumonia

SEVERE❖ Medical history❖ Family history❖ Physical and neurological exam❖ Lab tests❖ Tests for psychological, functional, and

cognitive status❖ MRI/PET/CT scan❖ CSF analysis

Ref: Alzforum, Alz.org, Podcasy et al., Dialogues Clin Neurosci. 2016;18:.437-446; alzdiscovery; usagainstalzheimers; alzsd; NIA

The final stage in which symptoms of Alzheimer’s, such as memory loss, word-finding difficulties, and visual/spatial problems, are significant, their presence are enough to impair a person’s ability to function independently.

As per NIA, Alzheimer in updated diagnostic guidelines

Preclinical

Mild cognitive

impairment (MCI)

Alzheimer’s dementia

Brain changes, amyloid building and changes in nerve cells, conslusiveclinical evidence need to be established

Memory or other thinking problems are highlighted where their symptoms are greater than normal for a person’s age and education, MCI may or may not progress to Alzheimer’s dementia.

Diagnosis

Unlike other responded therapeutic area where diagnosis is established, Alzheimer’s identity is still un-diagnosed

Three stages

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19

66

15

35

65

19

67

14

43

57

13

67

20

47

53

15

62

22

48

52

<65 65-84 >=85 MALE FEMALE

Risk category by age in cognitive patients

Normalcognition

Impaired,not MCI

MCI Dementia

Ref: Alz.org; alzheimersanddementia.com

Developing AD in US (every seconds)

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017 66

66

67

67

68

68

69

70

71

70

$236

$214

$200

NA

NA

$259

$226

$203

$183

NA

AD economic costs (in billions)

Burden & Risk Categories (1)With no promising therapy, Alzheimer’s cases are increasing; ages are making worse, economic costs keep increasing by year

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29,606,707

36,069,616

WORLD

6,034,130

4,794,610

AMERICAS

234,390

268,040

OCEANIA

19,369,569

17,018,637

ASIA

1,988,398

2,427,241

AFRICA

5,570,669

7,970,634

EUROPE

(65+ age group, using UN Population database and applying age range & Alzheimer occurrence as only filter criteria, these numbers could be different depending on the nature of

epidem model used and applied cut off criteria; by 2017)

Considering 65+ as sensitive age group of Alzheimer’s Disease, by 2017, a rough yet descriptive age numbers across geographies define the big numbers, probably this is why world is trying best to get rid of this mysterious & unidentified disease.

Reference: CDC, Alz.org, UN Population

Burden & Risk Categories (2)>65 age are most sensitive age group with Alzheimer’s, low-middle-high income geographies, all are being affected by Alzheimer’s

In US & as per CDC/Alz.org PR, in 2015, worldwide annual cost exceed $818 bn, Medicare and Medicaid pay nearly 70% of applicable cost related with Alzheimer’s; it is expected by 2050 annual costs can cross >$1.1 trillion, with >400% increase in annual costs to Medicare while >350% increase on out of pocket costs, Alzheimer’s is a huge burden on society.

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AgeneBio;Levetiracetam

Novartis;CNP520

Last 10 years industrial involvement in Advance phase of Alzheimer’s disease

Baxalta -Shire;Immune Globulin

Biogen; Aducanumab

Eli Lilly; Lanabecestat; Solanezumab; Semagacestat

Forum Pharma; Encenicline

H. Lundbeck A/S; Idalopirdine

Intra-Cellular Therapies; Lumateperone

Janssen;Bapineuzumab; Galantamine

Merck; Verubecestat; Suvorexant

Otsuka; Brexpiprazole; Aripiprazole

Roche; Crenezumab;Gantenerumab

Samsung Medical Center; Udenafil

Shanghai Greenvalley; Sodium Oligo-mannurarate

vTv Therapeutics; Azeliragon

Whanin Pharma; INM-176

1,2,3

2 1, 5 6

7 2

2 8 9

2 12 4 14

1

TauRx Therapeutics; TRx0237

Axovant; Intepirdine

Accera, Inc.;Tricaprilin

Biohaven;Trigriluzole

Eisai;Elenbecestat

Mitsubishi; Encenicline

Pfizer;Dimebon

13 15

1 16

14

20

21

Avanir; Dextromethorphan

Axsome;AXS-05

Icure Pharma; Donepezil*

Merz Pharma;Memantine

Shandong Luye;Huperzine

SK Chemicals; SK-PC-B70M

Takeda;Pioglitazone

11

11 4,18

17

1819

13

AZTherapies, Inc.; ALZT-OP1a/b

2

36,388,154

4,415,63710,828,652

13,541,157

502,424

1. BACE

2. Amyloid beta

3. γ-secretase

5. DORA

6. Dopamine

7. 5-HT6

8. PDE5

9. 5-HT2A

10. Tau

11.NMDA/σ1/HT,NE/nicotinic α3β4

12. RAGE

14. Nicotinic α7AchR agonist

13. 5-HT6

15. Glucose

16. SV2A

17. Anti-oxidant

18. NMDA

19. PPARγ

20. Glutamate

21. Hst.1/Ca2+ channels/AMPA/NMDA/Adr/HT/DR

Prone age group population

2,4

4. AChE

10

Quest in clinical trials - Industry

The total possible Alzheimer’s population is high, conclusive novel targets still missing in advanced industrial clinical trials

Reference: clinicaltrials.gov, UN Population

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Last 10 years academic involvement in Advance phase of Alzheimer’s disease

University of South Florida; Coconut Oil

3

University of Washington; Testosterone, Atabecestat

1,2

University of Southern California; Insulin

4

Charite University; Epigallocatechin-Gallate

7

Nanjing Medical University;Ginkgo biloba

9

University Hospital, Bonn; Bupropion

11

Banner Health;Thalidomide

7

St. James's Hospital;Nilvadipine

14

Imperial College;Guanfacine

16

Depression/Alzheimer’s

2. BACE

2. AChE

3. Glucose

4. Insulin

5. Arachidonic acid

6. SSRI;

Neurotransmitter

7. Amyloid beta

8. NGF

9. Antioxidant

11. Dopamine

13. Cannabinoid

14. Ca2+ channel

15. NaSSA

16. α2AdrR

Sunnybrook Health; Nabilone

Shanghai Mental Health Center;Octohydroaminoacridine Succinate

2

VA Office of R&D; Eicosapentaenoic Acid

5

JHSPH; Citalopram; Escitalopram

6

University Hospital, Angers; Cholecalciferol

7,8

Federal University; Rivastigmine

3

13

University of Sussex; Mirtazapine

15

Prone age group

1. Androgen

Quest in clinical trials - Academic

36,388,154

502,424

4,415,637

13,541,157

10,828,652

The total possible Alzheimer’s population is high, conclusive novel targets still missing in advanced academic clinical trials

Reference: clinicaltrials.gov, UN Population

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Aricept

Exelon

Razadyne

Namenda

Namzaric

2000

2001

2003

2014

AChEIs NMDA antagonist

Approvals are still around Anti-cholinesterases & NMDA, the approval timeline explains difficulties in around Alzheimer’s treatment.

Symptomatic treatment only

Reference: USFDA; Alz.org

Cognex

1993

High

Toxicities

Low-Medium

High

Prescription intenisty

Low-Medium

Yes

Generics availability

No

Mild-Moderate

Disease stage

Moderate- Severe

1996

*

* Preferences have been made by using FDA, annual reports & product comparison

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Do we need to follow conventional thinking in Alzheimer’s or it’s time to re-think outside the box?

“All the years of research & development are questioning success?”

Reference: Frozza et al., Front. Neurosci. 2018

Need of surrogate end points, genetic & biomarkers detailing, patient recruitment in clinical trials & early diagnosis are high unmet area, needed to address quickly & carefully

Although scientific knowledge has been extensively expanded on molecular & cellular bases of Alzheimer’s, target therapy is still missing, this has made to rethink Alzheimer’s and has questioned to sum up the findings.In advance phase of trials, Industries and Academics both were fighting to identify targets for Alzheimer’s. Amyloid stands to be favorite among industries and again, right therapy is still missing. On the other hand academia tried different targets for Alzheimer’s, but they run parallel to the Industries with a high failure rate.

At a time when more than 1500 trials have been conducted on Alzheimer’s and when right treatment is lacking, itbecomes questionable and time arrives to re-think on Alzheimer’s. Whether there is lack of pre-clinical models, failure ofclinical trials and toxicities are prime concern for Alzheimer’s study, end conclusion is still struggling to find right cure ofAlzheimer’s. The courageous and admirable efforts of industry and academia keeps falling, fainting future of Alzheimer’streatment. The funding in form of public-private partnership has emerged as a relief for the clinical trials while raise inchanges in policy makers can be identified as the unmet need for the treatment of Alzheimer’s.

Number of articles have asked questions around amyloid beta and clinical trial design, establishment of newer andprecise pre-clinical models which can mimic human, genes and surrogate end points. An era where personalizedmedicines are being highlighted, Alzheimer’s has still to walk a long distance.At a time when more than 1500 trials have been conducted on Alzheimer’s and when right treatment is lacking, itNumber of reports have highlighted dementia as a major problem in low and middle income countries, however, it needto be understand that 65+ age is distributed worldwide and it’s should be considered as the priority disease of theworld. The funding and initiatives across the globe explain severity of disease.

The failure rate is ~100% making one of this largest sensitive patient pool, never to forget the cost of burden thatAlzheimer’s contribute to society.

Conclusive story speaks around biomarkers, diagnosis, slow patient recruitment, clinical trials & other data findings. We have deepen our understanding of Alzheimer’s, but at the same time research failure has raised questions as:

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ALZHEIMER’S DISEASE- UPDATED INFO SHOT · A long history of findings & failures, raise in deaths, prevalence & costs, this is how Alzheimer’s is defined Ref: Alzforum, Alz.org